This project is directed at the determination of the structural requirements for the activity of DNA-binding drugs with specific emphasis on derivatives of bleomycin. Simple bleomycin analogs will be synthesized and studied for their ability to bind to and, under the appropriate conditions, to degrade DNA. Complexation will be studied using a variety of techniques, including fluorescence and NMR spectroscopy and equilibrium dialysis. The in vitro activity of these analogs will be tested against isolated DNA and synthetic polynucleotides as well as in cell systems. These data will allow the rational design of more effective and less toxic derivatives of the parent drug.